Journal of Innovations in Pharmaceuticals and Biological Sciences JIPBS

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ISSN: 2349-2759

Research article
Formulation and evaluation of floating drug delivery system of ramipril

Syed Iftequar*, Maria Saifee, Lahoti Swaroop, Zahid Zaheer, Sabina Meraj, Furqan khan,
Sarfraz Khan, Qazi Yasar, Shaikh Abdulla

Dr. Rafiq Zakaria Campus, Maulana Azad Educational Trust`s, Y. B. Chavan College of Pharmacy,
Post Bo.No. 33, Rauza Bagh, Aurangabad (Maharashtra) India.

Abstract
Oral drug delivery has been known for decades as the most widely utilized route of
administration among all the routes that have been explored for the systemic delivery of
drugs via various pharmaceutical products of different dosage forms. Gastro retentive drug
delivery systems are the systems which are retained in the stomach for a longer period of
time and thereby, improve the bioavailability of drugs. GRDDS can improve the controlled
delivery of drugs that have an absorption window by continuously releasing the drug for a
prolonged period of time before it reaches its absorption site, thus ensuring its optimal
bioavailability. Floating matrix tablet of Ramipril was prepared using HPMC K4M &
Carbopol 934NF. The NaHCO3 & Citric acid was used in combination as gas generating
agent. Sodium CMC was used as gelling agent. A 32 factorial design was applied for
preparing Formulation and evaluation of floating matrix tablet of Ramipril and to study the
effect of independent variables i.e. concentration of HPMC K4M [X1 (%w/w)] and
concentration of carbopol934NF [X2 (%w/w)] on various responses i.e. hardness, friability,
swelling and In-vitro drug release at Q8hr through matrix tablet. A constant complex weight
of 250 mg was incorporated in all the formulation batches. The In-vitro drug release of all
the formulation batches was determined by measuring the absorbance. The results
indicated that F9 showed least In-vitro drug release whereas F7 showed the highest release
of 98.6%. Infect higher amount of HPMC K4M in the complexes provided the formation of a
three dimensional hydrogel structure which was responsible for higher drug release.

Key words: GRDDS, Ramipril, HPMC K4M, Carbopol934NF, Sodium carboxymethylcellulose (Na
CMC), NaHCO3

*Corresponding Author: Syed Iftequar, Dr. Rafiq Zakaria Campus, Maulana Azad Educational
Trust`s, Y. B. Chavan College of Pharmacy, Post Bo.No. 33, Rauza Bagh, Aurangabad (Maharashtra)
India.

1. Introduction

Oral drug delivery has been known for delivery of drugs via various
decades as the most widely utilized route pharmaceutical products of different
of administration among all the routes that dosage forms. The reasons that the oral
have been explored for the systemic route achieved such popularity are its ease

©JIPBS, All rights reserved

 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016
of administration. In fact, the development
of a pharmaceutical product for oral
delivery, irrespective of its physical form
(solid, semi-solid or liquid dosage forms)
involves varying extents of optimization of
dosage forms characteristics within the
inherent constraints of GI physiology. [1]
Conventional oral dosage forms provide a
specific drug concentration in systemic
circulation without offering any control
over drug delivery. Controlled-release
drug delivery systems (CRDDS) provide
drug release at a predetermined,
predictable, and controlled rate. An
important requisite for the successful
performance of oral CRDDS is that the
drug should have good absorption
throughout the gastrointestinal tract,
preferably by passive diffusion, to ensure
continuous absorption of the released
drug. The average time required for a
dosage unit to traverse the GIT is 3 - 4 h,
although slight variations exist among
various dosage forms. The concept of
sustained or prolonged release of
biologically active agents has been well
appreciated and rationalized for decades.
In the exploration of oral controlled
release drug administration, one
encounters three areas of potential
challenge. [2]
1. Development of a drug delivery
system: To develop a viable oral
controlled release drug delivery
system capable of delivering a drug at
a therapeutically effective rate to a
desirable site for duration required for
optimal treatment. [4]
2. Modulation of gastro intestinal transit
time: To modulate the GI transit time
so that the drug delivery system
developed can be transported to a
target site or to the vicinity of an
absorption site and reside there for
prolonged period of time to maximize
the delivery of a drug dose. [8]
3. Minimization of hepatic first pass
elimination: If the drug to be delivered
is subjected to extensive hepatic first
pass elimination, preventive measures
should be devised to either bypass or
minimize the extent of hepatic
metabolic effect. [3]
2. Materials and Methods
Materials: Ramipril hydrochloride was
obtained as a gift sample (Shriya life
sciences Aurangabad. It is official in most
of the pharmacopoeia’s i.e. USP and BP. It
was standardized as per official
compendia and also characterized as per
Analytical profile of drug substance
provided by Florey.). Hydroxypropyl
methylcellulose K4M (HPMC K4M) and
Carbopol934NF were received as gift
samples from the Lobachemie, Mumbai.
All other ingredients used were of
analytical grade and were used as
received. [29]
Methods: Formulation Design: For
Simplex Centroid Design formulation
design expert 7.1.6 software (stat-ease)
demo version was used. In formulation
amounts of HPMC K4M (X1), Carbopol
934NF (X2) were selected as independent
variables. The floating lag time (FLT), and
times required for 50% of drug release
(t50) and 90% of drug release (t90) were
selected as dependent variables. In this
optimization study Quadratic mix order
and Scheffe design model were used.
The targeted response parameters were
statistically analyzed by applying one-way
analysis of variance (ANOVA) at 0.05
levels in Design-Expert 7.1.6 version soft
ware (Stat-Ease Inc., Minneapolis, MN).
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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

Stability studies tablets with hardness in range of 5 to 6

The best formulation was kept for stability kg/cm2. Tablets weighed 250 mg, and
studies in a stability chamber (Thermo were round flat-face with an average
lab) for a period of three months at diameter of 10 ± 0.1 mm and thickness of
temperature 400C ± 20C and RH 75 ± 5%. 3.4 ± 0.2 mm. 9 Formulations of the
The changes in physical appearance, factorial batches (F1 to F9) are shown in
weight, drug content, in-vitro drug release Table 3.
was observed after intervals of one
month. Table 1: Ramipril tablet formulation
Ingredients Qty./tablet Qty./20
Fabrication of Ramipril Hydrochloride (mg) tablet(mg)
floating tablets: Ramipril Floating tablets Ramipril 2.5 50
were formulated as per the formulations HPMC K4M 83.33 1666.6
given in Table 1. All the ingredients were Carbopol934NF 12.5 250
NaHCO3 25 500
weighed accurately. Drug was mixed with
Citric acid 12.5 250
required quantity of all ingredients by
Na CMC 8.3 166.66
geometric mixing. This blend was directly
Lactose 108.35 2117
compressed into tablets using 8.5-mm Talc 4.16 83.2
flat-face round tooling on Karnavati, 8 Mg-stearate 4.16 83.2
station RINEK rotary tablet press.
Compression force was adjusted to obtain

Table 2: Pre-compressional parameters for Ramipril gastro retentive tablets

FC Bulk Density Tapped Density Carr’s Index Angle of Repose
F1 0.750±0.04 0.865±0.02 13.29±0.04 29.05±0.14
F2 0.624±0.02 0.786±0.03 20.60±0.03 29.24±0.13
F3 0.636±0.03 0.769±0.02 17.29±0.02 26.84±0.14
F4 0.646±0.05 0.876±0.05 26.25±0.06 28.24±0.16
F5 0.634±0.03 0.824±0.05 23.05±0.07 28.36±0.16
F6 0.664±0.05 0.745±0.03 10.87±0.03 27.22±0.14
F7 0.630±0.03 0.789±0.02 17.49±0.02 26.15±0.14
F8 0.71±0.04 0.825±0.02 13.49±0.04 29.02±0.14
F9 0.614±0.02 0.786±0.03 21.60±0.03 27.24±0.13
Table 3: Composition of Ramipril gastro retentive factorial batches
Batches/Ingredients F1 F8 F9 F2 F4 F5 F3 F6 F7
Ramipril 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
HPMC K4M 50 50 50 75 75 75 100 100 100
Carbopol 934NF 7.5 12.5 17.5 12.5 17.5 7.5 17.5 12.5 7.5
NaHCO3 25 25 25 25 25 25 25 25 25
Citric acid 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5
Na CMC 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3
Lactose 126.6 121.6 116.6 96.68 91.68 101.6 66.6 71.6 76.68
Talc 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16
Mg-stearate 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16 4.16
Total(mg) 250 250 250 250 250 250 250 250 250

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

Ramipril gastro retentive factorial batches
were prepared by using two different
variables i.e. HPMCK4M and
Carbopol934NF their varying conc. are
given in the tab. Batches F1, F8, and F9
shows X1=50 mg HPMC K4M i.e. X1= -1,
similarly X1=0 in the Batches F2, F4 and
F5. X1= +1 in the batches F3, F6 and F7.
The X2 i.e. second variable is
carbopol934NF X2= -1 in the batches F1,
F5 and F7. X2=0 in the batches F2, F6 and
F8. similarly X2= +1 in the batches F3, F4
and F9.
Post-compressional parameters
The Post-compressional parameters like
thickness, hardness, friability, drug
Content and percent swelling are
calculated after formulation of each
factorial batch the values are given in the
Table 4. All the parameters are within the
prescribed limit.

Table 4 :Post -compressional parameters for Ramipril gastro retentive tablets

F Thickness Hardness Friability Average Drug Content Swelling (%)

F1 2.06± 0.04 4.0±0.02 0.28 248 97.46 89.2

F2 2.14± 0.08 4.0±0.04 0.36 251 98.42 86.44
F3 2.12±0.06 4.5±0.06 0.48 253 98.24 80.21

F4 2.08±0.02 4.2±0.02 0.56 248 99.58 88.66

F5 2.96± 0.04 4.3±0.04 0.34 247 99.84 84.01

F6 2.16± 0.06 4.0±0.04 0.64 252 97.56 86.42
F7 2.36± 0.06 4.3 ±0.02 0.61 247 97.8 98.69

F8 2.11± 0.07 4.5±0.07 0.52 248 98.9 87.25

F9 2.56± 0.09 4.4±0.06 0.32 255 92.4 81.44

In Vitro Buoyancy Studies: The in vitro dependent variables using statistical

buoyancy was determined by floating lag
time as per the method described by Rosa
et al, 10. The tablets were placed in a 100-
mL glass beaker containing simulated
gastric fluid (SGF), pH 1.2, as per USP. The
time required for the tablet to rise to the
surface and float was determined as
floating lag time.
3. Results
In the present investigation, combinations
of three polymers were studied using the
Quadratic design model. The
mathematical models developed for all the
analysis software.
In all Tablets batches (F1 to F9) floating
lag time variation were observed. Floating
lag time Polynomial equation magnitudes
of coefficients and mathematical signs
suggested significant effect on floating lag
time and varying amount of HPMC K4M,
Carbopol 934P, Sodium carboxy methyl
cellulose. As the amount of HPMC K4M
and sodium carboxy methylcellulose
increased, TFT increased; this is because
of increased gel strength of matrices due
to hydrophilic nature of HPMC, which
produces easy swelling of tablets, which

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

prevents escape of evolved carbon dioxide
from matrices, leading to decreased
density. Also the amount of Carbopol
934NF increased, TFT increased this may
be due to high affinity of carbopol towards
water, which promotes water penetration
into tablet matrices, leading to increased
density.
In Vitro Dissolution Studies: The in vitro
dissolution study of Ramipril
hydrochloride tablets was performed using
USP apparatus fitted with paddles (100
rpm) at 370C ± 0.50C using SGF (pH 1.2;
900 ml) as a dissolution medium. At the
predetermined time interval, 5-mL
samples were withdrawn, filtered through
a 0.45-μm membrane filter, diluted, and
assayed at 207.5 nm using a Shimadzu
UV/vis double-beam spectrophotometer.
There is a clear pharmaceutical need for
advanced delivery systems that
continuously supply narrow absorption
window drugs to their absorption site for
an extended time period. Provide effective
and sustained drug concentrations in the
blood for prolonged periods of time. It
would also eliminate the need for frequent
drug administration and the use of
inconvenient modes of administration (e.g.
parenteral infusion).
Optimizing the CR-GRDFs performance in-
vivo was based on in-vitro release
properties of the drug This IVIVC was
proven here as a practical tool to predict
the in-vivo release and absorption pattern
based on the GRDF design. Specifically, the
dose finding-study together with the - in
vitro release rate finding experiment was
carried out as follows: after the first
prototype (CR GRDF.
Kinetics of Drug Release: To study the
release kinetics from hydrogel based
matrix tablets, the release data were fitted
to the well-known exponential equation
(Korsmeyer–Peppas equation) and which
is often used to describe the drug release
behavior from polymeric systems when
the mechanism is not well known or when
more than one type of release
phenomenon is involved.

Table 5: In vitro drug release profile with minimum concentration of HPMC K4M
Percent drug release ± Std. Deviation (n=3)
Time (hours)
F1 F8 F9
1. 37.019±7.28 34.549±2.32 32.256±1.96
2. 40.400±3.67 57.32±1.04 40.197±1.35
3. 63.202±1.99 70.339±1.96 58.236±1.99
4. 71.489±1.35 73.02±1.99 63.672±3.67
5. 78.409±2.32 77.301±1.35 69.667±7.28
6. 80.954±1.96 80.546±3.67 72.87±1.42
7. 86.511±1.04 82.924±7.28 76.619±1.04
8. 89.273±1.42 87.254±1.42 81.444±2.32

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

Graph 1: In vitro drug release profile graph (minimum HPMC K4M) Series 1= F1 Series 2=
F8 Series 3= F9

Table 6: In vitro drug release profile with optimum concentration of HPMC K4M
Percent drug release ± Std. Deviation (n=3)
Time (hours)
F2 F4 F5
1. 31.198±7.28 29.963±1.96 40.37±2.32
2. 48.305±1.42 35.421±1.35 52.413±1.04
3. 68.682±3.67 62.959±1.99 65.581±1.96
4. 83.35±1.04 68.952±3.67 70.176±1.99
5. 86.102±1.99 75.858±7.28 75.147±1.35
6. 89.748±1.96 82.976±1.42 78.733±3.67
7. 95.882±2.32 87.31±1.04 81.807±7.28
8. 97.46±1.35 88.666±2.32 84.014±1.42

Graph 2: In vitro drug release profile graph (optimum HPMC K4M) Series 1= F2 Series 2= F4
Series 3= F5

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

Table 7: In vitro drug release profile with High concentration of HPMC K4M
Percent drug release ± Std. Deviation (n=3)
Time (hours)
F3 F6 F7
1. 52.895±1.04 43.898±7.28 31.198±1.42
2. 58.304±1.42 59.136±1.42 48.305±7.28
3. 67.976±7.28 68.107±3.67 68.682±3.67
4. 73.113±2.32 73.245±1.04 83.35±1.35
5. 76.689±3.67 77.175±1.99 86.102±1.99
6. 78.871±1.99 81.124±1.96 90.101±1.96
7. 81.063±1.35 83.682±2.32 95.354±1.04
8. 86.44±1.96 86.427±1.35 98.694±2.32

Graph 3: In vitro drug release profile graph (high HPMC K4M) Series 1= F3 Series 2= F6
Series 3= F7
Figure 3 shows release profile of simplex of formulations F7 exhibited zero-order
centroid batches. Formulations F1, F2, F3, release profile as their ‘n’ values were
F4, F5, F6 exhibited anomalous (non very close to 0.5681.
Fickian transport) diffusion/polymer
relaxation mechanism with a value Surface response plot:
ranging from 0.59 to 0.78. Whereas in case
Design-Expert® Software
Factor Coding: Actual
% drug release
Design points above predicted value
Design points below predicted value
98.69

80.21

X1 = A: hpmc k4m
% d r u g r e le a s e

X2 = B: carbopol 100

95

90

85

80

1.00

-1.00 0.50

-0.50 0.00
0.00
-0.50 B: carbopol
0.50
A: hpmc k4m 1.00 -1.00

Figure 1: Response surface plot (3D) showing the effect of the amount of amount of HPMC
K4M, CARBOPOL 934P and sodium carboxy methylcellulose on floating lag time, T50% and
T90% respectively

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016

Figure 1 shows the 3D surface plot of the
amount of HPMC K4M (X1), of Carbopol
934P (X2) and amount of sodium
carboxymethylcellulose (X3) versus %
Drug Release It may also be concluded
that the high level of X1 (amount of HPMC
K4M) and the lower level of X2 (amount of
carbopol 934P) and X3 (amount of sodium
carboxymethylcellulose) favor low
floating lag time. Time required release to
50% of drug (t50%) and time required
release to 90% of drug (t90%) showed
wide variation
DCS study:
DSC of Ramipril & Ramipril Tablet
Mixture:
DS C
mW
DSC thermogram of drug, and physical
mixture were obtained. Ramipril shows a
characteristic endothermic peak at
114.770C which corresponds to its
decomposition melt (Figure 2). DSC
thermogram of Ramipril and physical
mixture (Figure 3) showed an endotherm
at 154.040C corresponding to Ramipril
hydrochloride. The difference in thermal
peaks between the pure components and
physical mixture blend may be attributed
to sample geometry effects and to
reduction of individual purity in the
presence of other component). DSC
thermogram of Ramipril was found to be
similar to that given in Analytical profile
of drug substances by Florey (Figure2 and
Figure 3 respectively).
Temp
Thermal Analysis Result C

250.00

0.00
Ramipril.tad Temp
Ramipril.tad DSC

File Name: Ramipril.tad 200.00

0
Detector: DSC60
Start 105.99 x10
C Acq uisition Date 12/04/30
End 0
121.56 x10
C Acq uisition Time 16:15:15
-5.00 0
Sample N ame: Ramipril
Peak 114.77 x10
C Sample Weig ht: 2.940[mg ]
Onset 0
110.74 x10
C Annotation:
Endset 120.45 0
C
x10
Heat 0
-224.58 x10
mJ 150.00

-76.39 0
x10
J/g
Heig ht 0
-11.05 x10
mW
[Temp Prog ram]
Start Temp 100.0
-10.00 Temp Rate Hold Temp Hold Time
[C /min ] [ C ] [ min ]
20.00 250.0 0
100.00

0.00 2.00 4.00 6.00 8.00 10.00

Tim e [m in]

Figure 2: DSC of Ramipril

DS C Temp
mW Thermal Analysis Result C

0
Start 127.26 x10
C 250.00
Ramipr il tablet mixtur e.tad Temp
Ramipr il tablet mixtur e.tad DSC End 163.75 0
C
x10
Peak 0
154.04 x10
C
2.00
0
Onset 146.59 x10
C
[Temp Prog ram] 0
Start Temp 100.0 Endset 160.78 x10
C
Temp Rate Hold Temp Hold Time Heat - 139.59 0x10
mJ
[C /min ] [ C ] [ min ] 0
- 30.75 x10
J/g 200.00
20.00 250.0 0
0
Heig ht - 2.76 x10
mW
0.00
0
Start 174.32 x10
C
0
End 218.62 x10
C
0
Peak 196.72 x10
C
Onset 181.51 0
C
x10
150.00
Endset 213.03 0
C
x10
-2.00
0
File Name: Ramipr il tablet mixtur e.tad Heat - 311.84 x10
mJ
Detector : DSC60 - 68.69 0
x10
J/g
Acq uisition Date 12/04/30
Acq uisition Time 16:31:07 Heig ht - 3.80 0
x10
mW
Sample N ame: Ramipr il tablet mixtur e
Sample Weig ht: 4.540[mg ]
Annotation: 100.00
-4.00

0.00 2.00 4.00 6.00 8.00 10.00

Ti m e [m i n]

Figure 3: DSC of Ramipril Tablet Mixture

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 Syed Iftequar et al., JIPBS, Vol 3 (1), 85-95, 2016
4. Discussion
An attempt was made to develop a gastro
retentive drug delivery system of Ramipril
HCL using HPMC K4M, Carbopol 934P,
and Sodium carboxy methyl cellulose as
matrixing agent, viscosity increasing
agent, and gelling agent, respectively. A
simplex centroid design was applied to
investigate the combined effect of 3
formulation variables (i.e. amount of
HPMC (X1), Carbopol 934P (X2), and
sodium carboxymethyl cellulose (X3).
From the in vitro buoyancy studies, it was
found that almost all the batches
containing effervescent agent showed
immediate floatation followed by
floatation period of more than 18hr. The
values of diffusion exponent ‘n = 0.5681
determined from the Korsmeyer-Peppas
equations obtained from modeling of
dissolution profiles showing percent drug
release of a 90% indicates an anomalous
transport mechanism and that the mass
transfer follows a non Fickian model.
Conclusion
The effervescent based floating drug
delivery was a promising approach to
achieve in vitro buoyancy. The addition of
gel forming polymer (HPMC K4M) and gas
generating agent sodium bicarbonate and
citric acid were essential to achieve the in-
vitro buoyancy. The drug release form the
tablets were sufficiently sustained due to
the presence of polymers. Ramipril
hydrochloride floating tablet drug
delivery system showed improved in-vitro
bioavailability and extended drug release
which may favor the reduced dose
frequency and patient compliance. From
the results obtained, it was concluded that
the formulation F7 is the best
formulations as the extent of drug release
was found to be around 90 %. This batch
also showed immediate floatation and
floatation duration of more than 18hr. The
drug release model of this formulation
complies with zero order kinetics. Based
on the results we can certainly say that
floating type gastro retentive drug
delivery system holds a lot of potential for
drug having solubility as well as stability
problem in alkaline pH or which mainly
absorb in acidic pH. We can certainly
explore this drug delivery which may lead
to improved bioavailability and ensured
therapy with many existing drugs.
Acknowledgements
The authors are grateful to Maulana Azad
Education trust’s Y.B. Chavan College of
Pharmacy, Aurangabad for providing
essential laboratory conditions for
present research work. Also an author
acknowledges to Sherya labs Pvt. Ltd
(Aurangabad India), for providing gift
sample of Ramipril HCL.
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